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Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Vitamin B12 (cobalamin) is required for most human gut microbes, many of which are dependent on scavenging to obtain this vitamin. Since bacterial densities in the gut are extremely high, competition for this keystone micronutrient is severe. Contrasting with Enterobacteria, members of the dominant genus Bacteroides often encode several BtuB vitamin B12 outer membrane transporters together with a conserved array of surface-exposed B12-binding lipoproteins. Here we show that the BtuB transporters from Bacteroides thetaiotaomicron form stable, pedal bin-like complexes with surface-exposed BtuG lipoprotein lids, which bind B12 with high affinities. Closing of the BtuG lid following B12 capture causes destabilisation of the bound B12 by a conserved BtuB extracellular loop, causing translocation of the vitamin to BtuB and subsequent transport. We propose that TonB-dependent, lipoprotein-assisted small molecule uptake is a general feature of Bacteroides spp. that is important for the success of this genus in colonising the human gut. Uptake of vitamin B12 is important for colonisation of the gut by Bacteroides species. Here the authors characterise B12 uptake in Bacteroides thetaiotaomicron, mediated by outer membrane protein complexes consisting of surface-exposed BtuG lipoproteins and BtuB TonB-dependent transporters. [ABSTRACT FROM AUTHOR]

The need to support users of the Internet with the selection of information is becoming more important. Learners in complex, self-organising Learning Networks have similar problems and need guidance to find and select most suitable learning activities, in order to attain their lifelong learning goals in the most efficient way. Several research questions regarding efficiency and effectiveness deal with adequate navigation support through recommender systems. To answer some of these questions an experiment was set up within an Introduction Psychology course of the Open University of the Netherlands. Around 250 students participated in this study and were monitored over an experimental period of four months. All were provided the same course materials, but only half of them were supported with a personalised recommender system. This study examined the effects of the navigation support on the completion of learning activities (effectiveness), needed time to comply them (efficiency), actual use of and satisfaction with the system, and the variety of learning paths. The recommender system positively influenced all measures, by having significant effects on efficiency, satisfaction and variety. (Contains 7 figures and 4 tables.)

The traditional notion of the curriculum as a fixed list of topics to be studied sequentially is under strain as the pressure for flexibility in education increases. However, curriculum flexibility can lead to curriculum complexity, so that guidance systems are needed to assist learners in their study choices. This article proposes the use of the open, technical specification IMS Learning Design as a formal model for the description of curricula used by guidance support systems for learners. The article compares the approach to other work in the area, and illustrates its application with a number of case studies. The article concludes by describing the type of advanced guidance services which are enabled through a standardized approach and examining the e-learning infrastructure required when implementing the approach.

Efficient and effective lifelong learning requires that learners can make well informed choices from a vast amount of learning opportunities. This article proposes to support learners by drawing on principles of self-organization and indirect social navigation; by analysing choices made by learners who went before and feeding this information back as advice to present learners. A tool, developed to offer indirect social navigation through collaborative filtering, and tested in a controlled experiment, showed positive effects on effectiveness (progress and completion rates) though not on efficiency (time taken to complete and learners' perception of learning track efficiency). Learners in the experimental group were not faster at completing all available units of learning nor did they evaluate learning track efficiency more positively. Responses on the five-point scale measuring learning track efficiency seemed to indicate a dichotomy rather than an ordinal scale. Learners stated either that studying the units of learning in a different order might have led to increased understanding of the content or that a different order would not have led to greater efficiency. Analysing this dichotomy in relation to learning track characteristics by means of the decision tree induction data mining technique, revealed that a small subset of navigational choices discriminated between a positive evaluation on the one hand and doubts regarding the efficiency of the learning track on the other hand. These results suggest that positive effects for efficiency might be achieved, by incorporating learners' overall evaluations of learning tracks into the advice. (Contains 1 table and 3 figures.)

Purpose: This paper aims to define the need for a route modelling language in e-learning, identifying requirements and candidate languages, before providing a recommended approach. Design/methodology/approach: Several sources of requirements are drawn from the literature then used to review available approaches to route modelling. The best candidate is then applied in a number of case studies to check its applicability. Findings: An existing open standard, IMS learning design, is identified as meeting the requirements. To date the standard has been applied in a different area, so the match to the route modelling problem is favorable. Research limitations/implications: The scope of the work excluded an examination of requirements arising in the lifecycle management of routes; further investigation should check this point. Practical implications: Practical application is hampered by the lack of an appropriate e-learning infrastructure in which to apply the approach. Pilot infrastructures should become available in the next 18 months to two years. Originality/value: The work puts an existing e-learning specification in a new light, avoiding the need to develop a new language. Since tools and experience with the specification are already available, prospects for its adoption in a new role are favorable. (Contains 1 table and 3 figures.)

The outer membrane (OM) of Gram-negative bacteria forms a very efficient barrier against the permeation of both hydrophilic and hydrophobic compounds, owing to the presence of lipopolysaccharides on the outside of the cell. Although much is known about the OM passage of hydrophilic molecules, it is much less clear how hydrophobic molecules cross this barrier. Members of the FadL channel family, which are widespread in Gram-negative bacteria, are so far the only proteins with an established role in the uptake of hydrophobic molecules across the OM. Recent structural and biochemical research has shown that these channels operate according to a unique lateral diffusion mechanism, in which the substrate moves from the lumen of the barrel into the OM via an unusual opening in the wall of the barrel. Understanding how hydrophobic molecules cross the OM is not only of fundamental importance but could also have applications in the design of novel, hydrophobic drugs, biofuel production and the generation of more efficient bacterial biodegrader strains.